Lipoprotein(a): the cardiovascular risk you inherit

Some heart attacks arrive alongside an apparently impeccable blood test: cholesterol on target, blood pressure controlled, no diabetes and no smoking. In a proportion of those cases one figure is missing that the usual lipid profile does not capture: lipoprotein(a). It is an inherited particle, one that barely shifts over a lifetime and is raised in around one in five people. Knowing about it does not change anyone's genes, but it does change how prevention is approached.

What lipoprotein(a) is

Cholesterol does not travel loose in the blood: it moves inside particles called lipoproteins. The best known is LDL (low-density lipoprotein), the famous "bad cholesterol", which works its way into the artery wall and builds up atheromatous plaque.

Lipoprotein(a) —Lp(a) on laboratory reports— is essentially an LDL particle with an addition: an extra protein, apolipoprotein(a), attached to it like a long coiled tail. That seemingly minor detail changes everything, because it gives the particle two properties that ordinary LDL does not have.

On the one hand it is more atherogenic: it enters the arterial wall readily and carries oxidised phospholipids, molecules that stoke inflammation and speed up both the build-up and the rupture of plaque. On the other it is prothrombotic: apolipoprotein(a) resembles plasminogen, the precursor of plasmin —the enzyme that dissolves clots— and by taking up its place it hampers that natural clearing process. In short: a particle that soils the artery more and that also appears to hinder the mechanism which breaks clots down.

A level you are born with

Here lies the feature that sets it apart from the rest of the lipid profile: its concentration is determined in more than 80-90 % by genetics, specifically by the variants of the LPA gene inherited from both parents. It is established in childhood, reaches its adult value at around the age of five and stays practically stable for life.

That means diet, exercise, weight loss or giving up smoking —measures that improve almost everything else— barely alter it. Nor do statins, which lower LDL cholesterol very effectively but do not bring Lp(a) down; they may even raise it slightly, something seen in around 50-60 % of the people who take them. It is not a question of effort or discipline: it is the luggage you are born with. Hence the idea of inherited risk.

A few situations can shift the figure somewhat —chronic kidney disease, untreated hypothyroidism, hormonal changes— but they are the exception.

Why it matters

The large genetic and population studies of the past two decades have placed Lp(a) where it belongs: it is a causal and independent factor in cardiovascular disease. Independent means that it adds risk in its own right, even when LDL cholesterol, blood pressure and everything else are in order.

Raised levels are linked above all to three scenarios:

• Myocardial infarction and coronary disease, often at younger ages than would be expected.
• Ischaemic stroke (the kind caused by a blocked artery in the brain) and peripheral arterial disease.
• Calcific aortic stenosis: the progressive narrowing of the aortic valve through calcium deposition. Lp(a) is the lipid factor with the best-established causal link to this valve condition, though not the only one: genetic studies point to LDL cholesterol as well.

Risk here does not work like a switch but like a slope: the higher the figure, the greater the risk, and it is usually considered relevant from around 50 mg/dL (some 105 nmol/L; laboratories may report either unit, although the molar one is now preferred). This explains part of what is called residual risk: the events that occur in people whose conventional lipid profile looked flawless.

Who should have it measured, and how often

Measuring it is straightforward: an ordinary blood test, with no fasting or special preparation. It is not, however, part of the standard lipid profile and has to be requested specifically. European guidelines recommend measuring it at least once in a lifetime in adults, and there are situations in which it is especially worthwhile. You may recognise one of them:

• A family history of early cardiovascular disease: heart attacks or strokes before the age of 55 in men or 65 in women.
• Cardiovascular disease with no risk factors to explain it, or appearing at a young age.
• Familial hypercholesterolaemia (an inherited cholesterol disorder) or other severe abnormalities of the lipid profile.
• Intermediate cardiovascular risk, when the decision to start preventive treatment is not clear-cut and one extra piece of information may tip the balance.
• First-degree relatives of someone with raised Lp(a), given its hereditary pattern.

What to do if the result is high

It is worth being clear: there is at present no approved drug that lowers Lp(a) specifically and has shown that this reduction translates into fewer heart attacks or strokes. Several treatments aimed at it —therapies that curb its production in the liver— are at advanced stages of research and achieve very marked reductions, but the results confirming clinical benefit are still awaited. Only with extreme figures alongside progressive disease is apheresis used, a filtering of the lipoproteins.

In the meantime the strategy is a different one, and no less effective: if one factor cannot be moved, you press harder on all those that can. High Lp(a) does not change the type of prevention; it changes its intensity.

• LDL cholesterol: more demanding targets are pursued, because every point it falls offsets part of the added risk. Some of the drugs used for this, such as PCSK9 inhibitors, also bring Lp(a) down by around 20-25 %, although it has not been shown that this particular fall is what delivers the benefit.
• Blood pressure: strict, sustained control of high blood pressure.
• Smoking: stopping is the single most worthwhile measure, because it multiplies the effect of every other factor.
• Diabetes, weight, physical activity and diet: the usual pillars, with somewhat closer follow-up.
• Family screening: a high value justifies testing first-degree relatives —parents, siblings and children— who have roughly a 50 % chance of sharing it.

Information, not a sentence

A raised Lp(a) is neither a diagnosis of disease nor a verdict written in advance. Many people with high figures will never have a cardiovascular event, just as having a low one grants no immunity from smoking or uncontrolled blood pressure. What it offers is context: it places each person at their real starting point and makes it possible to decide, with better judgement, when to begin preventing, with what targets, and who else in the family should be tested.

And that is its greatest virtue: it can be known early, even decades before it shows itself, and that head start turns an inherited disadvantage into an advantage of time. It is not about living in thrall to a figure that cannot be changed, but about using it to look after everything else more carefully. Because the best medicine is still good prevention.

Sources and further reading

• Lipoprotein(a) — American Heart Association
• Guidelines on the management of dyslipidaemias — European Society of Cardiology
• High cholesterol — British Heart Foundation

This article is for information only and does not replace individual assessment or advice from a healthcare professional. For acute symptoms such as severe chest pain, call 112.